Pathergy Test


Pathergy phenomenon has been well known to dermatologists since it was first described in 1937 by Blobner as a state of altered tissue reactivity in response to minor trauma.[1] The pathergy test is a nonspecific hypersensitivity skin reaction induced by needle prick that is performed to look for evidence of this phenomenon. Pathergy lesions are generally manifested clinically by erythematous induration at the location of skin trauma, which may remain as papules or progress to sterile pustules. Although the precise mechanism of pathergy has not yet been entirely elucidated, the skin injury by needle prick in patients exhibiting pathergy is thought to trigger a cutaneous inflammatory response that is exaggerated and more prominent than that seen in normal skin. An increased release of cytokines from cells in the dermis or epidermis is implicated in this aberrant reaction, which results in the perivascular infiltrates that are characteristically observed on histopathologic studies.[2] While pathergy has been reported in numerous diseases, pathergy testing is primarily used in the diagnosis of Behcet Disease (BD).

Hulusi Behcet, a Turkish dermatologist, first characterized the clinical entity now known as BD by a triad of recurrent aphthous stomatitis, relapsing uveitis, and genital ulceration.[3] Since it was initially described in 1937, BD has come to be known as a multisystemic inflammatory disorder of unknown etiology with many additional cutaneous, gastrointestinal, articular, vascular, cardiopulmonary, and neurological manifestations. The mucocutaneous lesions of the disease often exhibit the pathergy reaction with the formation of new lesions or aggravation of previous ones following trivial trauma. However, pathergy is not restricted exclusively to the skin and can be more generally described as a state of disease hyperreactivity in any organ after injury.[4] Examples of the pathergy reaction in extracutaneous tissue sites of BD patients include the exacerbation of synovitis after arthrocentesis, the onset of uveitis following intraocular injections, and the formation of aneurysms around vascular anastomoses.

Along with BD, pathergy is also widely reported in various other disorders, including neutrophilic dermatoses such as pyoderma gangrenosum (PG) and Sweet syndrome.[1] In these other conditions, the term pathergy refers to the occurrence of lesions following trauma that closely parallel the pathology of the primary disease. This has some resemblance to the Koebner phenomenon that has been reported in other skin conditions and most well known in psoriasis. However, this is in contrast to the needle prick induced pathergy lesions seen in BD, which are usually histologically and grossly distinct from the lesions that naturally occur in the disease. Similar to other features of BD, pathergy is often seen in a relapsing-remitting pattern and is not always present throughout the disease course. There are significant variations in the prevalence of pathergy among different populations, and its incidence has been decreasing over the past few decades.[5] Nevertheless, pathergy testing is still one of the most vital components of the diagnostic criteria for BD.


As of now, there is still no standardized method of conducting the pathergy test. Intradermal, subcutaneous, and intravenous methods have all been used. Although intradermal needle prick is most commonly used for pathergy testing, many investigators have also used the intradermal injection of normal saline, monosodium urate crystals, or streptococcal antigens to perform the test.[6] Additionally, there are two types of pathergy tests; an oral pathergy test (OPT) and a skin pathergy test (SPT). For the OPT, the procedure entails pricking the mucous membrane of the lower lip to the level of the submucosa using a 20 gauge blunt disposable needle. Although the sensitivity of the OPT compared to the SPT has been reported to be lower, the OPT is arguably easier to assess since an ulcer or pustule of any size is considered positive, and there is no need to measure the size of the lesion.[3]

Although there is no consensus among clinicians, studies have shown that positive rates for the SPT can be increased by making at least two needle pricks on the hairless part of the volar forearm with a large hypodermic needle. The needle is usually inserted with the bevel up at an angle of 45 degrees to a depth of 3 mm to 5 mm.[1] The bevel should be obscured under the epidermis, and some clinicians recommend withdrawing the needle with a twisting movement.[7] Ozedemir et al. assessed the SPT in various body areas of patients with BD and concluded that the region with the most frequently positive tests is the forearm, and the least frequently positive region is the abdomen.[8] In their study, they also determined that the most considerable increase in positive pathergy reaction rates is with the application of a two-needle prick combination. Although the percentage of positive reactions can be increased with a higher number of pricks, the additional gain was minimal, and they concluded that two-needle pricks are sufficient for SPT. 

Furthermore, the diameter of the needle used has also been related to pathergy.[1] Whereas a 26 gauge disposable needle gave a 35.8% positive SPT in patients with BD, a 20 gauge needle elicited 62.5% positive reactions. Fine needles likely inflict insufficient trauma to reliably induce a pathergy reaction, and most clinicians recommend the use of a thick 20 gauge needle for SPT. Studies have also demonstrated that using a blunt (sterilized, reusable) needle increases the intensity and frequency of positive SPT when compared to disposable needles. However, the use of disposable needles is still preferred in clinical practice today to mitigate the risk of spreading blood-borne diseases with reusable blunt needles. Finally, some clinicians recommend against cleansing the skin with disinfectants prior to testing because surgical sterilization of the skin has reportedly decreased the positivity rate for SPT.[6]


Although the pathergy phenomenon is seen in various disease entities, pathergy testing is only indicated in establishing the diagnosis of BD. Once regarded as synonymous with BD, pathergy has decreased in prevalence over time and varies among different populations.[3] Because there are no pathognomonic laboratory tests for BD, diagnosis of the disease is made based on clinical findings. Numerous different clinical criteria have been proposed for BD, and a positive pathergy test is a crucial component of 12 of the 16 sets of criteria used to diagnose BD.[9] Among these, the most commonly used criteria are the International Study Group (ISG) and the Behcet Disease Research Group of Japan criteria.

The ISG criteria, most recently revised in 2006, has been validated to enable multicenter collaborations and reports values of 97% specificity and 92% sensitivity for BD.[1] This classification system attributes two points for each of the major criteria: genital aphthosis and ocular lesions (i.e., anterior uveitis, posterior uveitis, retinal vasculitis). One point is attributed to each of the minor criteria: oral aphthosis, positive pathergy test, skin manifestations (e.g., erythema nodosum-like lesions, pseudofolliculitis), and vascular lesions (i.e., phlebitis, superficial phlebitis, aneurysm, large vein thrombosis, arterial thrombosis).

Based on this scoring system, a diagnosis of BD is established by a sum of three or more points. Therefore, a pathergy test is indicated when an individual suspected of having BD exhibits only one of the major criteria or two or fewer of the minor criteria. For example, if a patient has a history of recurrent oral aphthosis (greater than 3 episodes per year) and pseudofolliculitis, a positive pathergy test can confirm the diagnosis of BD. However, if a different patient presents with recurrent oral aphthosis, uveitis, and genital aphthosis, a diagnosis of BD can be made without recourse to the pathergy test.[7] Nevertheless, the high specificity of a positive SPT makes this test an integral component of the diagnostic criteria for BD. Despite its indication in aiding the diagnosis of BD, pathergy testing has not been well established as a reliable means of tracking disease activity.[3] The utility of a positive pathergy test in predicting the clinical severity of disease and in modulating therapy for BD remains controversial and requires further investigation.

Potential Diagnosis

In the appropriate clinical context, a positive pathergy test should prompt consideration of BD on top of the differential diagnosis due to the high specificity of the test for the disease. The most common clinical feature of BD is the occurrence of recurrent, painful mucocutaneous ulcers (greater than 3 times a year). Oral aphthae are present in most patients with BD, but can also occur in other diseases such as systemic lupus erythematosus (SLE). Pathergy was once regarded as pathognomonic of BD because it was essentially absent in patients with SLE and recurrent aphthous stomatitis who presented with oral lesions akin to those seen in BD.[3] Aside from oral aphthosis and a positive pathergy test, other characteristic features that should raise suspicion for BD include, but are not limited to, genital aphthosis (typically scrotal lesions in men and vulvar lesions in women);  ocular disease (most commonly uveitis or retinal vasculitis); cutaneous manifestations (e.g., acneiform nodules, erythema nodosum-like lesions); vascular lesions (e.g., arterial and venous thrombosis, pulmonary artery aneurysms); and various neurological manifestations.[7] The low prevalence of the disease in non-endemic countries makes BD a challenging diagnosis to make, but one that can be made more confidently with a positive pathergy test in the context of recurrent aphthous ulcerations and a befitting constellation of systemic symptoms.

There have been various reports of the pathergy phenomenon in patients with chronic myeloid leukemia (CML) treated with interferon-alpha, atypical eosinophilic pustular folliculitis, myeloproliferative disorders, and in neonates with Down syndrome. A previous study showed that CML patients receiving treatment, specifically with interferon-alpha, had a high prevalence of positive pathergy tests (24%).[3] In this study, the specificity of pathergy testing for BD patients dropped from 98% to 92% when they included a group of patients with CML receiving interferon-alpha. These CML patients had tested negative before treatment with interferon-alpha. In BD patients receiving interferon-alpha, a higher rate of positivity was not seen when compared to BD patients taking cyclosporine A, colchicine, azathioprine, or no treatment. These results taken together may indicate a similarly altered neutrophil function in both interferon-alpha treated CML patients and BD patients.

Although pathergy testing has not been extensively studied in other disease entities, pathergy is a known feature of several other neutrophilic dermatoses, including pyoderma gangrenosum (PG), Sweet syndrome, erythema elevatum diutinum, and blind loop syndrome.[7] However, each of these dermatoses has its unique presentations and skin findings, so they are unlikely to be confused with BD simply based on a positive pathergy test. PG, for example, is an ulcerative skin disorder that is often associated with other systemic disorders, including inflammatory bowel disease, arthritis, and hematologic disorders. It most commonly presents as an inflammatory papule or pustule that can progress to a painful ulcer with a violaceous undermined border and a purulent base.[10] According to some studies, clinical pathergy was documented in nearly one-third of patients with PG. Sweet syndrome or acute febrile neutrophilic dermatosis, can present with fever, peripheral neutrophilia, a cutaneous eruption of erythematous papules and plaques, and a dermal non-vasculitic neutrophilic infiltration on biopsy.[11] The presence of pathergy in these other neutrophilic dermatoses may help provide insight into their pathogenesis and etiology. Moreover, the overall clinical context of the patient with a positive pathergy test is important because, under the right circumstances, it may help illuminate other diagnoses aside from BD.

Normal and Critical Findings

A physician ideally evaluates the pathergy test 24 to 48 hours after initial provocation. Erythema without any induration surrounding the needle prick site is considered normal, and thus a negative result.[6] For the SPT, a papule surrounded by an erythematous halo on the skin may be viewed as a positive result depending on the size of the papule. The papule can also transform into a pustule, which is considered a more strongly positive reaction. As mentioned before, the OPT is even easier to assess because an ulcer or pustule of any size is seen as a positive result.

Dilsen method of assessing and grading SPT is commonly used by clinicians and is based on the visible response on the skin 48 hours after needle prick.[1] Due to observations that sharpness of the needle often has a significant influence on the intensity of the reaction, the criteria used for assessment of blunt and sharp needle responses differ accordingly. For either type of needle, the SPT is considered negative if there is only erythema or trace of prick present on the skin. When a blunt needle is used, a papule less than 2 mm is considered neither positive nor negative, but rather “suspect.” Positive reactions are scored from 1+ to 4+ depending on the presence and size of erythematous papules or pustules. A grade of 1+ is assigned when a papule of 2 mm to 3 mm is observed with blunt needles, or a papule less than or equal to 3mm is observed with sharp needles. For both types of needles, any papule greater than 3 mm is graded 2+, pustules 1 mm to 2 mm graded 3+, and pustules greater than 2 mm graded 4+. However, the correlation between the strength of the positive SPT and disease severity or disease activity in BD remains uncertain.

Interfering Factors

Results of the pathergy test have been known to vary widely between populations and even between different investigators studying the same population. The positivity rate for pathergy tests in BD is highest in countries along the Silk Route, which includes the Middle East, Far East, and Mediterranean Basin.[6] By contrast, BD patients from the US, UK, and other Northern European nations have significantly lower reported rates for positive pathergy tests. Numerous studies have also demonstrated a decline in the prevalence of positive pathergy tests over time since the 1980s.[12] Genetic, environmental, and procedure-related variations have all been proposed as possible factors that can influence and interfere with pathergy testing.[3] 

One of the major interfering factors affecting results of pathergy testing is thought to be related to the materials and methods used to conduct the test. Various studies revealed that using a blunt (sterilized, reusable) needle increases the intensity and frequency of positive pathergy tests.[1] It is proposed that repeated sterilization in boiling water makes these needles rough due to an accumulation of calcium on the tips of the needles, which makes the blunt needles more traumatic than the disposable ones. The relatively lower rates of positive pathergy tests in BD patients from developed countries may be explained in part by the fact that blunt, reusable needles were used more extensively in underdeveloped countries before the 1980s.[3] Since 1985, the widespread use of disposable needles to prevent the spread of bloodborne infections is hypothesized to also partly account for the decrease in sensitivity of pathergy testing in BD patients over time.[12] As previously discussed, the diameter of the needle used in the procedure also influences the results of the testing, with the thicker 20 gauge needles inflicting more skin trauma and increasing the likelihood of inducing a positive result in BD patients. Additionally, surgical cleaning of the skin before needle prick has been shown to interfere with testing, causing a decreased positivity rate.[3] It appears that surgical sterilization, by an unknown mechanism, interferes with the pathergy reaction and can cause a suppression of the pathergy test. The lack of consensus on pathergy testing protocols as well as differences in interpretations of a positive test contributes to the differing rates of positivity among BD patients.

Another possible interfering factor with pathergy testing is thought to be the use of corticosteroids by BD patients, which can increase the false-negative results according to some studies.[12] However, other researchers have demonstrated that systemic corticosteroid use did not alter the histology or the gross appearance of the pathergy test. Several groups have also found that the pathergy test is more strongly positive among male patients compared to female patients of similar age.[3] They also showed that the age of disease onset did not affect the strength of the pathergy reaction. Another study indicated that although the results of the pathergy test had no association with any particular disease manifestation or with disease activity, the prevalence of positive pathergy tests was lower in milder cases of BD. It has also been shown that BD patients were more likely to have a positive test if they were not taking their medications for the disease at the time of testing.[1] Further investigations are still required to determine how various factors influence pathergy so that pathergy testing can be more refined to maximize sensitivity.


There have been no serious reported complications of the oral or skin pathergy test in BD patients. The papules and pustules that result from the skin prick usually become maximum in 48 hours and disappear within 45 days.[6] Therefore, pathergy testing itself is considered relatively harmless and does not cause any known adverse effects. However, the disruption of tissue integrity that triggers an exaggerated inflammatory response characteristic of the pathergy phenomenon has been associated with numerous complications in BD. In particular, eye inflammation following intraocular corticosteroid injections, superficial thrombophlebitis induced by venipuncture, aneurysm formation after angiographic interventions, lesions after vascular surgeries, and anastomotic ulcers following bowel resections are all well-known examples of adverse pathergy reactions in various tissue sites of BD patients.[3] The actual incidences of these known complications and their correlation with positive SPT have not been well established and merit future research efforts.

Complications related to pathergy in PG patients have also been well documented. Surgical debridement of PG ulcers has occasionally resulted in the rapid progression of the ulcers with an exponential increase in size.[1] There have also been reports of procedures such as venipuncture and intravenous line placement inducing new PG lesions in pathergy-like reactions. Thus, it is crucial to be aware of such complications related to pathergy in patients so that clinicians may minimize interventions that have the possibility of worsening their condition. Other studies have shown a positive pathergy test to be an independent risk factor for postoperative complications in patients with BD.[6] Surgical intervention may be required at times for BD when, for example, patients manifest ischemia from thromboembolism or have an impending aneurysm rupture. Under these circumstances, a positive pathergy test can help identify subgroups of patients at higher risk of postoperative complications and in guiding the initiation of immunosuppressive treatments in such patients.

Clinical Significance

Although pathergy testing has decreased in its sensitivity over the past few decades, it remains an invaluable test in the diagnosis of BD. Despite the loss in sensitivity, the test has demonstrated improvements in its diagnostic odds ratio, positive predictive value, and positive likelihood ratio.[12] Pathergy test is a crucial component of 12 of the 16 different sets of criteria used in the diagnosis of BD. Without its use, sensitivity and accuracy of diagnosis decrease, demonstrating that pathergy testing improves the power of existing diagnostic criteria.[9] Though the likelihood of positive findings has decreased over time, a positive pathergy test has demonstrated specificity as high as 98.4% for BD. Therefore, it is quite powerful in resolving various diagnostic dilemmas for diseases that may have a similar initial presentation. 

Despite the presence of pathergy clinically in other conditions, BD is the only disease that includes a positive pathergy test as part of its diagnostic criteria. Nevertheless, the knowledge of pathergy reaction in neutrophilic dermatoses such as PG and other disease entities is important because it may influence the diagnoses and assessment of these conditions. It would be of great interest to systematically study and perform pathergy tests in patients with these diseases because it may provide invaluable insight into their pathophysiology and possibly guide their management.[1] To date, many aspects of the pathergy reaction and its clinical correlates remain unclear and warrant an open-minded re-examination of the pathergy phenomenon in BD and other related conditions.

Article Details

Article Author

Shaoon Rahman

Article Editor:

Steven Daveluy


5/8/2022 2:20:14 AM



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